Type 2 diabetes (T2D) also known as diabetes mellitus is a growing health problem. Recent estimates indicate there were 171 million people in the world with diabetes in the year 2000 and this is projected to increase to 366 million by 2030 (Wild S, Roglic G, Green A, Sicree R, King H. Global Prevalence of Diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care. 2004, 27, 1047-1053). The classical treatment for type 2 diabetes developed over the past 20 years has been based on 2 types of oral anti-hyperglycemic drugs; sulfonylureas that stimulate insulin secretion and the biguanides that have a broad spectrum of effects, but act primarily on hepatic insulin resistance. Then, alpha glucosidase inhibitors (i.e. acarbose) have been developed which decrease the intestinal absorption of glucose. A new category of molecules has appeared called thiazolidinediones (TZD). They act through binding and activation of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ). More recently, the recognition that hormones secreted by the gut play a role in maintaining blood glucose homeostasis has led to emergence of several novel class of medications acting as analogs of the incretin glucagon-like peptide (GLP-1) or as inhibitors of its degradating enzyme dipeptidyl peptidase IV (DPP-IV inhibitors) stabilizing its half-life. GLP-1 is an incretin hormone causing enhanced post-prandial insulin secretion, but also known to have a range of additional effects including reduced gastric motility and appetite suppression, which indirectly impact on glucose metabolism in vivo (Drucker, D. J.; Sherman, S. I.; Bergenstal, R. M.; Buse, J. B., The safety of incretin-based therapies—review of the scientific evidence. J Clin Endocrinol Metab 2011, 96, 2027-2031. Baggio, L. L.; Drucker, D. J., Biology of Incretins: GLP-1 and GIP. Gastroenterology 2007, 132, 2131-2157). These new incretin-based medications offer the advantage of highly successful efficacy associated with an exceedingly favorable side effect profile and neutral effects on weight (Cefalu, W. T., Evolving treatment strategies for the management of type 2 diabetes. Am J Med Sci 2012, 343, 21-6. Gallwitz, B., Glucagon-like peptide-1 analogues for Type 2 diabetes mellitus: current and emerging agents. Drugs 2011, 71, 1675-88).
Despite the use of various hypoglycemic agents, current treatments often fail to achieve sufficient lowering of serum glucose and/or are often associated with deficiencies including hypoglycemic episodes, gastrointestinal problems, weight gain, and loss of effectiveness over time (El-Kaissi, S.; Sherbeeni, S., Pharmacological management of type 2 diabetes mellitus: an update. Curr Diabetes Rev 2011, 7, 392-405).
In this context, the bile acid receptor TGR5 appears as an emerging and promising therapeutic target (Chen X Fau-Lou, G.; Lou G Fau-Meng, Z.; Meng Z Fau-Huang, W.; Huang, W., TGR5: A Novel Target for Weight Maintenance and Glucose Metabolism. Exp Diabetes Res. 2011, 2011: 853501. Pols Tw Fau-Noriega, L. G.; Noriega Lg Fau-Nomura, M.; Nomura M Fau-Auwerx, J.; Auwerx J Fau-Schoonjans, K.; Schoonjans, K., The bile acid membrane receptor TGR5: a valuable metabolic target. Dig. Dis. 2011, 29, 37-44. Porez, G.; Prawitt, J.; Gross, B.; Staels, B. J. Lipid Res. 2012, 53, 1723-1737). TGR5 (also named Gpbarl or M-BAR) (Maruyama, T.; Miyamoto, Y.; Nakamura, T.; Tamai, Y.; Okada, H.; Sugiyama, E.; Nakamura, T.; Itadani, H.; Tanaka, K., Identification of membrane-type receptor for bile acids (M-BAR). Biochem. Biophys. Res. Commun 2002, 298, 714-719. Kawamata, Y.; Fujii, R.; Hosoya, M.; Harada, M.; Yoshida, H.; Miwa, M.; Fukusumi, S.; Habata, Y.; Itoh, T.; Shintani, Y.; Hinuma, S.; Fujisawa, Y.; Fujino, M., A G Protein-coupled Receptor Responsive to Bile Acids. J. Biol. Chem. 2003, 278, 9435-9440) is a member of the G-protein coupled receptor (GPCR) family. TGR5 is broadly expressed in human tissues, including those that are not usually known as targets of bile acids. In particular, TGR5 is highly expressed in adipose tissue, muscle and enteroendocrine cells. A body of evidence supports a role for TGR5 in energy homeostasis. Indeed, administration of bile acids to mice increased energy expenditure in the brown adipose tissue and prevented diet-induced obesity and insulin-resistance. This effect was ascribed to a cAMP dependant intra-cellular induction of the type 2 iodothyronine deiodase (D2) enzyme, which converts inactive thyroxine (T4) into active 3,5,5′-tri-iodothyronine (T3). By this pathway, bile acids increase energy expenditure in part through activation of mitochondrial function in brown adipose tissue and skeletal muscle, hence preventing obesity and resistance to insulin (Watanabe, M.; Houten, S. M.; Mataki, C.; Christoffolete, M. A.; Kim, B. W.; Sato, H.; Messaddeq, N.; Harney, J. W.; Ezaki, O.; Kodama, T.; Schoonjans, K.; Bianco, A. C.; Auwerx, J., Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006, 439, (7075), 484-489). Consistent for a role of TGR5 in energy homeostasis, female TGR5 deficient mice although not obese under chow fed conditions, showed significant fat accumulation with body weight gain compared to wild-type mice when fed a high fat diet (Maruyama, T.; Tanaka, K.; Suzuki, J.; Miyoshi, H.; Harada, N.; Nakamura, T.; Miyamoto, Y.; Kanatani, A.; Tamai, Y., Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbarl/M-Bar) in mice. Journal of Endocrinology 2006, 191, 197-205). Moreover, it was shown that oleanolic acid, a component of olive oil that binds to and activates TGR5, lowers glucose and insulin levels in mice fed with a high fat diet and enhances glucose tolerance (Sato, H.; Genet, C.; Strehle, A.; Thomas, C.; Lobstein, A.; Wagner, A.; Mioskowski, C.; Auwerx, J.; Saladin, R., Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea. Biochem. Biophys. Res. Commun 2007, 362, 793-798). Very interestingly, bile acids and compounds that affect TGR5 activity have been shown to increase GLP-1 secretion from enteroendocrine intestinal cells (Katsuma, S.; Hirasawa, A.; Tsujimoto, G. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1 Biochem. Biophys. Res. Commun. 2005, 329, 386-390). More recently, using a combination of pharmacological and genetic gain- and loss-of-function studies in vivo, Thomas et al. (Thomas, C.; Gioiello, A.; Noriega, L.; Strehle, A.; Oury, J.; Rizzo, G.; Macchiarulo, A.; Yamamoto, H.; Mataki, C.; Pruzanski, M.; Pellicciari, R.; Auwerx, J.; Schoonjans, K., TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 2009, 10, 167-177) showed that TGR5 signaling induced GLP-1 release also in vivo, leading to improved liver and pancreatic function and enhanced glucose tolerance in obese mice. Therefore, pharmacological targeting of TGR5 may constitute a promising incretin-based strategy for the treatment of diabesity and associated metabolic disorders. Interestingly, in addition to its expression in enteroendocrine L cells and its incretin secretagogue activity, TGR5 has also been shown to be expressed in inflammatory cells and its activation leads to anti-inflammatory effects and to anti-atherosclerotic effects in mouse. (Kawamata, Y.; Fujii, R.; Hosoya, M.; Harada, M.; Yoshida, H.; Miwa, M.; Fukusumi, S.; Habata, Y.; Itoh, T.; Shintani, Y.; Hinuma, S.; Fujisawa, Y.; Fujino, M., A G Protein-coupled Receptor Responsive to Bile Acids. J. Biol. Chem. 2003, 278, 9435-9440. Keitel, V.; Donner, M.; Winandy, S.; Kubitz, R.; Haussinger, D., Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun 2008, 372, 78-84. Pols, T. W. H.; Nomura, M.; Harach, T.; LoA Sasso, G.; Oosterveer, M. H.; Thomas, C.; Rizzo, G.; Gioiello, A.; Adorini, L.; Pellicciari, R.; Auwerx, J.; Schoonjans, K., TGR5 Activation Inhibits Atherosclerosis by Reducing Macrophage Inflammation and Lipid Loading. Cell Metabolism 2007, 14, (6), 747-757).
TGR5 agonists including natural or semi-synthetic bile acids (Pellicciari, R.; Gioiello, A.; Macchiarulo, A.; Thomas, C.; Rosatelli, E.; Natalini, B.; Sardella, R.; Pruzanski, M.; Roda, A.; Pastorini, E.; Schoonjans, K.; Auwerx, J., Discovery of 6-Ethyl-23(S)-methylcholic Acid (S-EMCA, INT-777) as a Potent and Selective Agonist for the TGR5 Receptor, a Novel Target for Diabesity J. Med. Chem. 2009, 52, 7958.7961), bile alcohols, triterpenoid compounds such as oleanolic acid, betulinic acids (Genet, C. d.; Strehle, A.; Schmidt, C. I.; Boudjelal, G.; Lobstein, A.; Schoonjans, K.; Souchet, M.; Auwerx, J.; Saladin, R. g.; Wagner, A. Structure-Activity Relationship Study of Betulinic Acid, A Novel and Selective TGR5 Agonist, and Its Synthetic Derivatives: Potential Impact in Diabetes J. Med. Chem. 2010, 53, 178-190), nomilin (Ono, E.; Inoue, J.; Hashidume, T.; Shimizu, M.; Sato, R. Anti-obesity and anti-hyperglycemic effects of the dietary citrus limonoid nomilin in mice fed a high-fat diet. Biochem. Biophys. Res. Commun. 2011, 410, 677-681) or avicholic acid and synthetic nonsteroidal small molecules (Gioiello, A.; Rosatelli, E.; Nuti, R.; Macchiarulo, A.; Pellicciari, R., Patented TGR5 modulators: a review (2006-present). Expert Opin Ther Pat 2012, 22, (12), 1399-1414) have been described recently.
However, safety concerns for some systemic TGR5 agonists were recently mentioned. Hyperplasia of the gall bladder which becomes enlarged due to delayed emptying, increased filling, or a combination of these effects was reported by investigators working with systemic TGR5 agonists in mouse models. Li, T.; Holmstrom, S. R.; Kir, S.; Umetani, M.; Schmidt, D. R.; Kliewer, S. A.; angelsdorf, D. J. The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling. Mol. Endocrinol. 2011, 25, 1066-1071, Duan, H.; Ning, M.; Chen, X.; Zou, Q.; Zhang, L.; Feng, Y.; Zhang, L.; Leng, Y.; Shen, J., Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists. Journal of Medicinal Chemistry 2012, 55, (23), 10475.
More recently, it was reported that TGR5 stimulation in skin by systemic agonists triggers intense pruritus, comparable to the effect of the naturally occurring bile acids during cholestasis (Alemi, F.; Kwon, E.; Poole, D. P.; Lieu, T.; Lyo, V.; Cattaruzza, F.; Cevikbas, F.; Steinhoff, M.; Nassini, R.; Materazzi, S.; Guerrero-Alba, R.; Valdez-Morales, E.; Cottrell, G. S.; Schoonjans, K.; Geppetti, P.; Vanner, S. J.; Bunnett, N. W.; Corvera, C. U., The TGR5 receptor mediates bile acid-induced itch and analgesia. The Journal of Clinical Investigation 2013, 123, (4), 1513). Consequently, a much lower systemic exposure or even a non systemic exposure may be necessary for the development of a nontoxic TGR5 agonist.
International patent application WO 2011/071565 describes imidazole and triazole based TGR5 agonists having a quaternary ammonium moiety.
There is however still a need for new compounds that may be of therapeutic value in the treatment of TGR5 related diseases, such as T2D and conditions that are associated with this disease including, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.